The overall goal of this proposal is to elucidate the mechanisms by which chronic viral infection mediates telomere loss and T cell aging that may cause vaccine failure, with an aim to develop effective means to improve vaccine efficacy in virally infected individuals. To this end, we will use a model of HBV vaccine responses in the setting of HIV infection. Due to shared risk factors, co-infection of HBV with HIV is common; as such, HBV vaccine is required to prevent co-infection and associated morbidity and mortality. HBV vaccine responses in HIV-infected individuals are, however, often blunted, with only 30-60% seroconversion (HBsAb > 10 IU/ml) compared to a 90-95% success rate in healthy subjects (HS). This poor vaccine response is also observed for influenza and pneumococcal vaccinations in HIV patients and in other immunocompromised hosts, including the elderly. Attempts to improve the immunizations in both infected and aged humans have been unsuccessful, in part due to our poor understanding of the mechanisms that can dampen vaccine responses in these settings. Recently, we and others have found that chronic viral (HIV, HCV) infection is often associated with an accelerated premature T cell aging, as demonstrated by overexpression of aging markers (such as KLRG1, DUSP6, and p16ink4a), decline of age-associated miR-181a and, in particular, accelerated loss of telomeres - suggesting excessive proliferative turnover or inadequate telomere maintenance, when compared to age-matched HS. Telomere integrity is a key feature of linear chromosomes that preserves genome stability and function, whereas telomere erosion is a hallmark of cell aging or senescence that drives cell dysfunction or apoptosis. While telomere length is maintained in most cases by telomerase that prolongs telomeric DNA, telomeric repeat binding factor 2 (TRF2) is required to protect telomeres from unwanted DNA damage response (DDR). Notably, DNA damage repair enzymes (ATM/ATR) are involved in the DDR. To date, how telomeric DNA damage and repair signaling pathways are dysregulated in the context of HIV infection and their roles in T cell aging or HBV vaccine failure remain largely unknown. In this proposal, we hypothesize that i) telomere loss and T cell aging play a pivotal role in HBV vaccine failure in HIV-infected individuals; and ii) telomerase insufficiency, TRF2 uncapping-mediated telomeric DDR, and lack of ATM/ATR-dependent telomeric DNA repair accelerate T cell aging in HIV infection; thus restoring these telomeric machineries will open new avenues to protecting T cells from aging and maintaining immune competence. To test this hypothesis, we will: 1) characterize the role of telomere loss and T cell aging in HBV vaccine failure during HIV infection; 2) define the mechanisms underlying telomeric DNA damage emanating from HIV infection. This translational study is significant in that it will provide a working model to explore mechanisms that may be fundamental to diminishing immune (vaccine) responses that are observed in many chronic infectious diseases, including but not limited to HIV infection. Understanding such mechanisms is critical for developing approaches to improve vaccine response in the setting of chronic HIV infection.